SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Atrovent® 250 UDVs®, 1 ml Atrovent® UDVs®, 2 ml

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

Each single dose unit contains 0.025 % w/v ipratropium bromide i.e. 250 micrograms in 1 ml and 500 micrograms in 2 ml.

3    PHARMACEUTICAL FORM

Nebuliser solution.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Atrovent UDVs are indicated for treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD).

Atrovent UDVs are indicated, when used concomitantly with inhaled beta2-agonists, for the treatment of reversible airways obstruction as in acute and chronic asthma.

4.2    Posology and method of administration

The dosage should be adapted to the individual needs of the patient. In children aged 12 years and under, only Atrovent 250 UDV’s, 1ml should be used. The following doses are recommended:

Adults (including the elderly) and children over 12 years of age:

250-500 micrograms (i.e. one vial of 250micrograms in 1ml or one vial of 500micrograms in 2ml) 3 to 4 times daily.

For treatment of acute bronchospasm, 500micrograms.

Repeated doses can be administered until the patient is stable. The time interval between the doses may be determined by the physician.

It is advisable not to exceed the recommended daily dose during either acute or maintenance treatment. Daily doses exceeding 2mg in adults and children over 12 years of age should only be given under medical supervision.

Children 6-12 years of age:

250 micrograms (i.e. one vial of 250 micrograms in 1ml) up to a total daily dose of 1 mg (4 vials).

The time interval between doses may be determined by the physician.

Children 0-5 years of age (for treatment of acute asthma only):

125 -250 micrograms (i.e. half to one vial of 250 micrograms in 1ml) up to a total daily dose of 1mg (4vials).

Ipratropium bromide should be administered no more frequently than 6 hourly in children under 5 years of age.

For acute bronchospasm, repeated doses may be administered until the patient is stable.

If therapy does not produce a significant improvement or if the patient’s condition gets worse, medical advice must be sought. In the case of acute or rapidly worsening dyspnoea (difficulty in breathing) a doctor should be consulted immediately.

ATROVENT UDVs may be combined with a short-acting beta₂ agonist in the same nebuliser chamber for simultaneous administration where coadministration is required. The solution should be used as soon as possible after mixing and any unused solution should be discarded.

ATROVENT UDVs can be administered using a range of commercially available nebulising devices. The dose of nebuliser solution may need to be diluted in order to obtain a final volume suitable for the particular nebuliser being used; if dilution is necessary use only sterile sodium chloride 0.9% solution.

AROVENT UDVs and disodium chromoglycate inhalation solutions that contain the preservative benzalkonium chloride should not be administered simultaneously in the same nebuliser as precipitation may occur.

Administration

The unit dose vials are intended only for inhalation with suitable nebulising devises and should not be taken orally or administered parentally.

1. Get your nebuliser ready by following the manufacturers instructions and the advice of your doctor.

2.    Carefully separate a new dose unit from the strip. NEVER use one which has been opened already.

3.    Open by simply twisting of the top, always taking care to hold it in an upright position.

4.    Unless otherwise instructed by your doctor, squeeze all the contents into the nebuliser chamber. If you have been prescribed a short-acting beta2 agonist nebuliser solution, the solutions can be combined in the same nebuliser chamber. If dilution is necessary this should be carried out using only sterile sodium chloride 0.9% solution and as instructed by your doctor.

5.    Use your nebuliser as instructed by your doctor.

6.    After you have finished, throw away any left over solution or partially used vials. Follow the manufacturer’s instructions for cleaning your nebuliser. It is important that your nebuliser is kept clean.

4.3 Contraindications

Known hypersensitivity to atropine or its derivatives, or to any other

component of the product.

4.4. Special warnings and precautions for use

Use of the nebuliser solution should be subject to close medical supervision during initial dosing.

Immediate hypersensitivity reactions following the use of ATROVENT have been demonstrated by cases of urticaria, angioedema, rash, bronchospasm, oropharyngeal oedema and anaphylaxis.

Caution is advocated in the use of anticholinergic agents in patients predisposed to or with narrow-angle glaucoma, or with pre-existing urinary outflow tract obstruction (e.g. prostatic hyperplasia or bladder-outflow obstruction).

As patients with cystic fibrosis may be prone to gastro-intestinal motility disturbances, ATROVENT, as with other anticholinergics, should be used with caution in these patients.

There have been isolated reports of ocular complications (i.e. mydriasis, increased intra-ocular pressure, narrow-angle glaucoma, eye pain) when aerosolised ipratropium bromide, either alone or in combination with an adrenergic beta2-agonist, has come into contact with the eyes during nebuliser therapy.

Eye pain or discomfort, blurred vision, visual halos or coloured images in association with red eyes from conjunctival congestion and corneal oedema may be signs of acute narrow-angle glaucoma. Should any combination of these symptoms develop, treatment with miotic drops should be initiated and specialist advice sought immediately.

Patients must be instructed in the correct administration of ATROVENT UDVs. Care must be taken not to allow the solution or mist to enter the eyes. It is recommended that the nebulised solution is administered via a mouthpiece. If this is not available and a nebuliser mask is used, it must fit properly. Patients who may be predisposed to glaucoma should be warned specifically to protect their eyes.

As with other inhalation therapy, inhalation induced bronchoconstriction may occur with an immediate increase in wheezing after dosing. This should be treated straight away with a fast acting inhaled bronchodilator. ATROVENT UDVs should be discontinued immediately, the patient assessed and, if necessary, alterative treatment instituted.

4.5 Interaction with other medicinal products and other forms of interaction

There is evidence that the administration of Atrovent with beta-adrenergic drugs and xanthine preparations may produce an additive bronchodilatory effect

The risk of acute glaucoma in patients with a history of narrow-angle glaucoma (see Special Warnings and Precautions for Use) may be increased when nebulised ipratropium bromide and beta₂-agonists are administered simultaneously.

4.6    Fertility, pregnancy and lactation

The safety of ATROVENT during human pregnancy has not been established. The benefits of using ATROVENT during a confirmed or suspected pregnancy must be weighed against the possible hazards to the unborn child. Preclinical studies have shown no embryotoxic or teratogenic effects following inhalation or intranasal application at doses considerably higher than those recommended in man.

It is not known whether ipratropium bromide is excreted into breast milk. It is unlikely that ipratropium bromide would reach the infant to an important extent, however caution should be exercised when ATROVENT is administered to nursing mothers.

Preclinical studies performed with ipratropium bromide showed no adverse effect on fertility (see section 5.3). Clinical data on fertility are not available for ipratropium bromide.

4.7    Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. However, patients should be advised that they may experience undesirable effects such as dizziness, accommodation disorder, mydriasis and blurred vision during treatment with ATROVENT. If patients experience the above mentioned side effects they should avoid potentially hazardous tasks such as driving or operating machinery.

4.8 Undesirable Effects

Many of the listed undesirable effects can be assigned to the anticholinergic properties of ATROVENT. As with all inhalation therapy ATROVENT may show symptoms of local irritation. Adverse drug reactions were identified from data obtained in clinical trials and pharmacovigilance during post approval use of the drug.

The most frequent side effects reported in clinical trials were headache, throat irritation, cough, dry mouth, gastro-intestinal motility disorders (including constipation, diarrhoea and vomiting), nausea, and dizziness.

Frequencies

Very common Common Uncommon Rare

Very rare

> 1/10

> 1/100 < 1/10 > 1/1,000< 1/100 > 1/10,000 < 1/1,000 < 1/10,000

⁽¹⁾    ocular complications have been reported when aerolised ipratropium bromide, either alone or in combination with an adrenergic beta₂-agonist, has come into contact with the eyes - see section 4.4.

⁽²⁾    As with other inhalation therapy, inhalation induced bronchoconstriction may occur with an immediate increase in wheezing after dosing. This should be treated straight away with a fast acting inhaled bronchodilator. ATROVENT UDVs should be discontinued immediately, the patient assessed and, if necessary, alterative treatment instituted.

⁽³⁾    the risk of urinary retention may be increased in patients with pre-existing urinary outflow tract obstruction.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard

4.9 Overdose

No symptoms specific to overdosage have been encountered. In view of the wide therapeutic window and topical administration of ATROVENT, no serious anticholinergic symptoms are to be expected. As with other anticholinergics, dry mouth, visual accommodation disturbances and tachycardia would be the expected symptoms and signs of overdose.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

ATROVENT is a quaternary ammonium compound with anticholinergic (parasympatholytic) properties. In preclinical studies, it appears to inhibit vagally mediated reflexes by antagonising the action of acetylcholine, the transmitter agent released from the vagus nerve. Anticholinergics prevent the increase in intracellular concentration of Ca++ which is caused by interaction of acetylcholine with the muscarinic receptor on bronchial smooth muscle. Ca++ release is mediated by the second messenger system consisting of IP3 (inositol triphosphate) and DAG (diacylglycerol).

The bronchodilation following inhalation of ATROVENT is induced by local drug concentrations sufficient for anticholinergic efficacy at the bronchial smooth muscle and not by systemic drug concentrations.

In clinical trials using metered dose inhalers in patients with reversible bronchospasm associated with chronic obstructive pulmonary disease significant improvements in pulmonary function (FEV₁ increases of 15% or more) occurred within 15 minutes, reached a peak in 1-2 hours, and persisted for approximately 4 hours.

Preclinical and clinical evidence suggest no deleterious effect of ATROVENT on airway mucous secretion, mucociliary clearance or gas exchange.

The bronchodilator effect of ATROVENT in the treatment of acute bronchospasm associated with asthma has been shown in studies in adults and children over 6 years of age. In most of these studies ATROVENT was administered in combination with an inhaled beta₂-agonist.

5.2 Pharmacokinetic Properties

Absorption

The therapeutic effect of ATROVENT is produced by a local action in the airways. Time courses of bronchodilation and systemic pharmacokinetics do not run in parallel.

Following inhalation, 10 to 30% of a dose is generally deposited in the lungs, depending on the formulation, device and inhalation technique. The major part of the dose is swallowed and passes through the gastro-intestinal tract.

The portion of the dose deposited in the lungs reaches the circulation rapidly (within minutes).

Cumulative renal excretion (0-24 hrs) of parent compound is approximated to 46% of an intravenously administered dose, below 1% of an oral dose and approximately 3 to 13% of an inhaled dose. Based on these data the total systemic bioavailability of oral and inhaled doses of ipratropium bromide is estimated at 2% and 7 to 28% respectively.

Taking this into account, swallowed dose portions of ipratropium bromide do not contribute significantly to systemic exposure.

Distribution

The drug is minimally (less than 20%) bound to plasma proteins. The quarternary amine of the ipratropium ion does not cross the blood-brain barrier.

Biotransformation

Ipratropium has a mean total clearance of 2.3 L/min and a renal clearance of 0.9 L/min. After intravenous administration approximately 60% of the dose is mainly metabolised by conjugation (40%), wheras after inhalation about 77% of the systemically available dose is metabolised by ester hydrolysis (41%) and conjugation (36%).

Elimination

After inhalation of ipratropium bromide either with HFA 134a or CFC propellant, cumulative renal excretion over 24 hours was approximately 12% and 10%, respectively.

In an excretion balance study cumulative renal excretion (6 days) of drug-related radioactivity (including parent compound and all metabolites) accounted for 72.1% after intravenous administration, 9.3% after oral administration and 3.2% after inhalation. Total radioactivity excreted via the faeces was 6.3% following intravenous application, 88.5% following oral dosing and 69.4% after inhalation. Regarding the excretion of drug-related radioactivity after intravenous administration, the main excretion occurs via the kidneys. The half-life for elimination of drug-related radioactivity (parent compound and metabolites) is 3.2 hours. The main urinary metabolites bind poorly to the muscarinic receptor and have to be regarded as ineffective.

5.3 Preclinical safety data

The toxicity of ipratropium bromide has been investigated extensively in the following types of studies: acute, subchronic and chronic toxicity, carcinogenicity, reproductive toxicity and mutagenicity via oral, intravenous, subcutaneous, intranasal and/or inhalation routes. Based on these toxicity studies, the probability of systemic anticholinergic side effects decreases in the following order:

intravenous > subcutaneous > oral > inhalation > intranasal.

Pre-clinically, ipratropium bromide was found to be well-tolerated. Two-year carcinogenicity studies in rats and mice have revealed no carcinogenic activity at doses up to approximately 1,200 times the maximum recommended human daily dose for intranasal ipratropium. Results of various mutagenicity tests were negative.

Studies to investigate the possible influence of ipratropium bromide on fertility, embryo-fetotoxicity, and peri-/postnatal development have been performed on mice, rats and rabbits. High oral levels, i.e. 1000 mg/kg/day in the rat and 125 mg/kg/day in the rabbit were maternotoxic for both species and embryo-/fetotoxic in the rat, where the fetal weight was reduced. Treatment-related malformations were not observed. The highest, technically feasible doses for inhalation of the metered dose aerosol, 1.5 mg/kg/day (human equivalent dose of 0.24 mg/kg/day) in rats and 1.8 mg/kg/day (human equivalent dose of 0.576 mg/kg/day) in rabbits, showed no adverse effects on reproduction.

These doses are 6- and 14-fold the maximum recommended human daily dose (MRHDD) of 2 mg or 0.04 mg/kg (based on a body weight of 50 kg).

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium Chloride 1N Hydrochloric Acid Purified Water

6.2 Incompatibilities

None stated.

6.3    Shelf life

24 months (unopened).

As the product contains no preservative, a fresh vial should be used for each dose and the vial should be opened immediately before administration. Any solution left in the vial should be discarded.

6.4    Special precautions for storage

Do not store above 25°C. Keep vials in the outer carton.

Nature and contents of container

Polyethylene unit dose vials packed in cartons. Each single dose unit contains either 1 ml or 2 ml of solution in pack sizes of 10, 20, 30, 50, 60, 80, 100, 120, 150, 200, 300, 500 and 1000.

Pack sizes of 20 and 60 are currently marketed.

6.6 Special precautions for disposal

None.

7 MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim Limited

Ellesfield Avenue

Bracknell

Berkshire

RG12 8YS

8    MARKETING AUTHORISATION NUMBER(S)

PL 00015/0108

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

23/12/2005

10 DATE OF REVISION OF THE TEXT

28/07/2014